Microglial extracellular vesicles induce Alzheimer's disease-related cortico-hippocampal network dysfunction

?-Amyloid is one of the main pathological hallmarks of Alzheimer's disease and plays a major role in synaptic dysfunction. It has been demonstrated that ?-amyloid can elicit aberrant excitatory activity in cortical-hippocampal networks, which is associated with behavioural abnormalities. However, the mechanism of the spreading of ?-amyloid action within a specific circuitry has not been elucidated yet. We have previously demonstrated that the motion of microglia-derived large extracellular vesicles carrying ?-amyloid, at the neuronal surface, is crucial for the initiation and propagation of synaptic dysfunction along the entorhinal-hippocampal circuit. Here, using chronic EEG recordings, we show that a single injection of extracellular vesicles carrying ?-amyloid into the mouse entorhinal cortex could trigger alterations in the cortical and hippocampal activity that are reminiscent of those found in Alzheimer's disease mouse models and human patients. The development of EEG abnormalities was associated with progressive memory impairment as assessed by an associative (object-place context recognition) and non-associative (object recognition) task. Importantly, when the motility of extracellular vesicles, carrying ?-amyloid, was inhibited, the effect on network stability and memory function was significantly reduced. Our model proposes a new biological mechanism based on the extracellular vesicles-mediated progression of ?-amyloid pathology and offers the opportunity to test pharmacological treatments targeting the early stages of Alzheimer's disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.